The present invention relates to prodrugs, pharmaceutical compositions comprising said prodrugs as well as their use as a medicament for treating or preventing diseases or disorders which can be treated by insulin.
Insulin therapy is characterized by a high need for keeping the insulin drug release within very strict levels as the therapeutic window is narrow, and the adverse effects of hyperinsulinemia can potentially be life threatening. Numerous insulin preparations have been commercialized, with different action profiles to suit specific needs of the diabetic population. Fast acting insulin analogs are administered just before meals, in order to control the peak in plasma glucose following food ingestion, whereas long acting insulin analogs are typically given once or twice a day to provide a steady basal insulin level.
Therefore, there is a clear need for novel long acting preparations of insulin, that continuously release insulin throughout the entire period between administrations.
WO-A 2006/003014 describes a hydrogel capable of releasing insulin with the possibility of reduced dosing frequency as compared to standard daily basal insulin injections. However, the insulin is released at a rate too fast for ensuring strict insulinotropic control for periods extending 2 days. In fact the insulin is released with a half life of approximately 30 hours, meaning that the prodrug must be administered at least every 30 hours in order for the peak to trough ratio to be below 2 at steady state.
The concept of preparing a reversible polymer prodrug conjugate of insulin has been explored by Shechter et al. and described in scientific articles and patent applications (e.g. European Journal of Pharmaceutics and Biopharmaceutics 2008(70), 19-28 and WO-A 2004/089280). The insulin is conjugated to a 40 kDa PEG polymer through a fluorenyl-linker. Hydrolysis of said linker molecule releases insulin with a half life of approximately 30 hours, meaning that the prodrug must be administered at least every 30 hours in order for the peak to trough ratio to be below 2 at steady state.
Other attempts of reducing the insulin dosing frequency have been made. Hinds et al., Journal of Controlled Release, 2005 (104), 447-460, describe a method of producing a once weekly insulin, by first permanently PEGylating the insulin molecule and then subsequently microencapsulating the PEGylated insulin in PLGA microparticles. In this case, the insulin was subjected to substantial structural modification through permanent modification by a high molecular weight polymer entity. Such high molecular weight modified insulins may exhibit reduced efficacy by diminished receptor binding and may also exhibit injeciton site reactions such as lipoatrophy due to the extended presence of high concentrations of the high molecular weight insulin in the subcutaneous tissue. Furthermore, such PEGylated insulins will exhibit a lower distribution volume, which is of particular disadvantage in the treatment of diabetes.
Nevertheless, PEGylation of insulin apparently serves to protect the peptide from deterioration in the PLGA polymer formulation. The effect of PEGylation to protect peptides from acylation in a degrading PLGA formulation was demonstrated for octreotide by D. H. Na et al., AAPS PharmSciTech 2003, 4 (4) Article 72.
PLGA encapsulation of proteins has been shown to cause side reactions of the polymer esters with peptide or protein amino groups. Lactic acid acylation products have been observed after exposure of the formulations to buffered solutions at neutral pH (G. Zhu et al., Nature Biotechnology 18 (2000) 52-57; A. J. Domb et al., Pharm. Res. 11 (1994) 865-868; A. Lucke et al., Pharm. Res. 19 (2002) 175-181).
Specifically for insulin, detrimental effects of polymer formulations have been demonstrated by P. G. Shao et al., Pharm. Dev. Technol. 4 (1999) 633-642 (see also P. G. Shao et al., Pharm. Dev. Technol. 5 (2000) 1-9).
Furthermore, insulin is known to readily undergo side reactions that are related to the presence of three disulfide bridges in the molecule. For instance, insulin may be split into A and B chains by disulfide bond cleavage or dimers or oligomers may be formed due to disulfide interchange reactions. Such disulfide reshuffling is particularly likely, if insulin molecules are forced into close contact in a random way. This intrinsic lability of the insulin molecule has significantly hampered progress in long-acting depot development and prevented the use of other polymer formulations where insulin is encapsulated in a way similar to an amorphous precipitate which is well known to give rise to various degradation products arising from extensive disulfide exchange.
Therefore the challenge remains to develop long-acting insulin without compromising the insulin pharmcacodynamics by permanent attachment of a high molecular weight entity or by causing structural damage to the molecule while during its presence in the depot.
Thus an object of the present invention is to provide an insulin containing prodrug that meets at least partially the above requirements.